Cell Clearing Systems As Targets of Polyphenols in Viral Infections Potential Implications For COVID-19 Pathogenesis

7.0 8.
Review
Cell Clearing Systems as Targets

of Polyphenols in Viral Infections:
Potential Implications for COVID-19
Pathogenesis
Fiona Limanaqi, Carla Letizia Busceti , Francesca Biagioni, Gloria Lazzeri, Maurizio Forte,
Sonia Schiavon, Sebastiano Sciarretta, Giacomo Frati and Francesco Fornai
Special Issue
Modulation of Autophagy by Dietary Polyphenols: Mechanisms and Health Benefits
Edited by
Dr. Elzbieta Janda
https://doi.org/10.3390/antiox9111105
antioxidants
Review
Cell Clearing Systems as Targets of Polyphenols in
Viral Infections: Potential Implications for
COVID-19 Pathogenesis
Fiona Limanaqi 1 , Carla Letizia Busceti 2 , Francesca Biagioni 2 , Gloria Lazzeri 1 ,
Maurizio Forte 2 , Sonia Schiavon 3 , Sebastiano Sciarretta 2,3 , Giacomo Frati 2,3
and Francesco Fornai 1,2, *
1 Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa,
Via Roma 55, 56126 Pisa, Italy; f.limanaqi@studenti.unipi.it (F.L.); gloria.lazzeri@unipi.it (G.L.)
2 I.R.C.C.S. Neuromed Pozzilli, Via Atinense, 18, 86077 Pozzilli, Italy; carla.busceti@neuromed (C.L.B.);
francesca.biagioni@neuromed.it (F.B.); maurizio.forte@neuromed.it (M.F.);
sebastiano.sciarretta@uniroma1.it (S.S.); fraticello@inwind.it (G.F.)
3 Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome,
Corso della Repubblica 79, 40100 Latina, Italy; sonia.schiavon@uniroma1.it
* Correspondence: francesco.fornai@unipi.it or francesco.fornai@neuromed.it

Received: 4 October 2020; Accepted: 8 November 2020; Published: 10 November 2020
Abstract: The novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
has generated the ongoing coronavirus disease-2019 (COVID-19) pandemic, still with an uncertain
outcome. Besides pneumonia and acute lung injury (ALI) or acute respiratory distress syndrome
(ARDS), other features became evident in the context of COVID-19. These includes endothelial
and coagulation dysfunction with disseminated intravascular coagulation (DIC), and multiple
organ dysfunction syndrome (MODS), along with the occurrence of neurological alterations.
The multi-system nature of such viral infection is a witness to the exploitation and impairment
of ubiquitous subcellular and metabolic pathways for the sake of its life-cycle, ranging from host
cell invasion, replication, transmission, up to a cytopathic effect and overt systemic inflammation.
In this frame, alterations in cell-clearing systems of the host are emerging as a hallmark in the
pathogenesis of various respiratory viruses, including SARS-CoV-2. Indeed, exploitation of the
autophagy and proteasome pathways might contribute not only to the replication of the virus at the
site of infection but also to the spreading of either mature virions or inflammatory mediators at both
cellular and multisystem levels. In this frame, besides a pharmacological therapy, many researchers
are wondering if some non-pharmacological substances might counteract or positively modulate
the course of the infection. The pharmacological properties of natural compounds have gained
increasing attention in the field of alternative and adjunct therapeutic approaches to several diseases.
In particular, several naturally-occurring herbal compounds (mostly polyphenols) are reported to
produce widespread antiviral, anti-inflammatory, and anti-oxidant effects while acting as autophagy
and (immuno)-proteasome modulators. This article attempts to bridge the perturbation of autophagy
and proteasome pathways with the potentially beneficial effects of specific phytochemicals and
flavonoids in viral infections, with a focus on the multisystem SARS-CoV-2 infection.
Keywords: autophagy; immunoproteasome; coronavirus; inflammation; resveratrol; quercetin;

kaempferol; baicalin; cordycepin
Antioxidants 2020, 9, 1105; doi:10.3390/antiox9111105 www.mdpi.com/journal/antioxidants

Antioxidants 2020, 9, 1105 2 of 35
1. Introduction
The coronavirus disease 2019 (COVID-19), generated by the novel coronavirus named SARS-CoV-2,
emerged as a rapidly spreading communicable disease, still with an uncertain outcome worldwide.
Similar to other respiratory viruses, including influenza viruses and the two other members of the
Coronaviridae family SARS-CoV and MERS-CoV, SARS-CoV-2 produces multifaceted, often severe
effects in the human body [1,2]. A considerable number of patients affected by COVID-19 develops
severe respiratory complications due to interstitial pneumonia and acute lung injury (ALI)/ acute
respiratory distress syndrome (ARDS) with lung vasculitis and respiratory failure, which are associated
with a high mortality rate [2,3]. The respiratory symptoms caused by SARS-CoV-2 are similar to that of
influenza virus, SARS-CoV, and MERS-CoV infection, being associated with rapid lung inflammation
and overt cytokine storm [1,3,4]. Besides pneumonia and ARDS/ ALI, multiple-organ damage along
with the occurrence of neurological alterations, have become more and more evident in the context of
COVID-19 [5–10]. As documented by autopsy studies, the vascular insult is devastating even within
the lung itself, and a marked inflammatory response within blood vessels is observed [5,8]. COVID-19
symptoms also include cardiovascular events, such as stroke, multiple thromboembolism, as well
as acute myocarditis, and myocardial infarction, even in the absence of lung involvement [6,11–15].
SARS-CoV-2 might trigger an exacerbated immunological response and cytokine storm, leading to
a “viral sepsis” [16], which can indirectly contribute to cardiovascular injury and might explain
the causes of cardiac and vascular damage. Nonetheless, similar to other coronaviruses (CoVs),
SARS-CoV-2 might also directly infect cardiomyocytes, endothelial cells, and pericytes, thereby
causing progressive myocardial damage and vasculitis characterized by extensive thrombosis [16–18].
In either case, the severe involvement of blood vessels is expected to spread the disease within various
organs, preferring those with a high blood supply. Either a direct viral infection or a cytokine storm
spreading through a synapse-connected route might also explain the central nervous system (CNS)
alterations that are observed during SARS-CoV-2 infection [19–21]. SARS-CoV-2 was detected in the
cerebrospinal fluid and also within neuronal and endothelial brain cells of COVID-19 patients [19,20].
The neuro-invasive potential of SARS-CoV-2 is not fully characterized, though it appears reminiscent of
that of SARS-CoV [21–23]. In detail, SARS-CoV produces a massive infection of the brainstem in both
patients and experimental animals [24,25]. In light of the high similarity with SARS-CoV, it is expected
that SARS-CoV-2 produces similar effects. The kind of neurological symptoms reported in COVID-19
patients [9,10] appears to be compatible with this scenario. As reported for SARS-CoV, the involvement
of a few neurons within the ventrolateral medulla, which generates the cardiorespiratory rhythm,
might affect the cardiovascular and respiratory systems, even following small focal damage of the
brainstem [24,25]. In this way, the CNS, which provides profuse innervation to multiple organs
including the lung, the heart, and blood vessels themselves, might contribute to generating and
sustaining the multi-system disorder associated with SARS-CoV-2 infection.
This is compatible with the specific yet widespread placement of the angiotensin-converting
enzyme type 2 (ACE2), which represents the gateway for SARS-CoV-2 entry within infected cells.
In fact, ACE2 is abundantly expressed in the lungs, heart, kidney, vasculature, and cardiorespiratory
neurons within the brainstem [18,26,27]. The ACE2 receptor might provide the opportunity to
the virus for multi-organ infectivity, resulting in multiple organ dysfunction syndrome (MODS),
through impairment of ubiquitous subcellular structures and metabolic machinery to complete its
life-cycle and transmission.
Despite controversial results, the occurrence of alterations in cell-clearing pathways is emerging
as a hallmark in the pathogenesis of numerous respiratory viruses, including influenza virus,
MERS-CoV, SARS-CoV, and SARS-CoV-2 [28–34]. This is the case of the ubiquitin-proteasome
system (UPS) and autophagy, which recently attracted much attention as potential therapeutic
targets in COVID-19 pathogenesis [30–32,34–37]. Within eukaryotic cells, autophagy and the UPS
operate coordinately, to clear intracellular damaged proteins, organelles, and also bacterial and
viral pathogens [38,39]. Autophagy and the UPS are also promiscuously implicated in innate and
adaptive immunity, by modulating constitutive inflammatory responses while ensuring antigen

processing and plasma membrane presentation to CD4+ and CD8+ T-cells via MHC-II and MHC-I
molecules, respectively [39–43]. In this scenario, autophagy and proteasome configure as sentinels
in the mechanisms underlying cell-to-cell, and multi-system communication in both health and
disease [39,44]. Both autophagy and UPS are commonly altered in several inflammatory-related
conditions, including viral infections as well as pulmonary, metabolic, cardiovascular, and neurological
diseases [30,33,34,38,41,44–48]. Thus, understanding how SARS-CoV-2 alters these pathways,
might contribute to disclosing the specific failure that occurs within different cell types, reflecting the
multi-organ/multi-system nature of COVID-19.
Identifying new targets and drugs against SARS-CoV-2 represents a rush against time since no
therapies are shown to be fully effective and devoid of adverse effects [49]. The need for natural-based
autophagy modulators was recently emphasized in the frame of COVID-19 pathogenesis [31,35]. In this
context, the effects of naturally-derived compounds have become an area of immense interest, due to
their multi-system-multi-target, mostly anti-inflammatory and anti-oxidant effects, coupled with a
relatively safe toxicity profile at potentially therapeutic doses [50–55]. In detail, several naturally
occurring compounds (mostly polyphenols) from traditional herbal medicine (THM), are reported
to produce beneficial effects in various inflammatory disorders, including viral infections, as well
as respiratory, cardiovascular, and neurological diseases [55–67]. Remarkably, the main bioactive
compounds of these formulas, such as resveratrol, quercetin, kaempferol, baicalin, and cordycepin,
while counteracting viral replication and abnormally activated inflammatory/apoptotic pathways,
do act as autophagy or UPS modulators as well [57,67–73].
The present review focuses on the potential link between the effects of specific phytochemicals and
the tuning of autophagy and UPS pathways in the frame of the multi-system disorder produced by CoV
infections. The article covers autophagy/UPS-related and phytochemical-targeted molecular pathways
that are potentially implicated in the SARS CoV-2 viral gateways, its fruitful replication within host
cells, inflammatory and oxidative alterations affecting cell function and viability, and eventually,
the extracellular spreading of the virus and viral-induced inflammatory mediators. Dissecting the
molecular mechanisms through which autophagy/UPS-modulating phytochemicals might provide
beneficial effects in respiratory viral infections and inflammatory-related conditions might contribute to
disclosing potential targets and hopefully, to developing prophylactic or adjunct therapeutic strategies
in multisystem COVID-19.
2. What We Know, Do Not Know, and What We Can Hypothesize on the Role of Autophagy and
Proteasome in Viral Infections and COVID-19 Pathogenesis
2.1. Autophagy, Viral Infection, and Inflammation

Autophagy is an evolutionarily-conserved intracellular mechanism that mediates degradation of
misfolded proteins, intracellular aggregates, and damaged organelles through a complex degradative
process that plays a crucial role in eukaryotic cell homeostasis. Autophagy is activated in response
to cellular stresses, including starvation, endoplasmic reticulum (ER) stress, and oxidative stress,
thereby limiting or modulating cell death. Accordingly, several cytoplasmic elements such as proteins,
lipids, sugars, nucleic acids, senescent or damaged organelles, or pathogens, are isolated and enclosed
into a double-membrane nascent vacuole called phagophore, which then matures to seal in the
autophagosome. Autophagy machinery might be initiated either as a non-selective process or
involve several adaptor/receptor proteins such as SQSTM1/p62, which deliver ubiquitinated cargoes,
and also the proteasome itself, to the forming autophagosome [48,54]. P62 represents an autophagy
substrate that is widely hired as a marker of autophagy flux progression, which follows up the fusion
of autophagosomes/amphisomes with lysosomes. In fact, the mature autophagosome fuses with
endosomes and multivesicular bodies (MVBs) giving origin to the amphisome, which eventually
fuses with the lysosome that provides acidic hydrolases for substrate breakdown. Once engulfed
within the autolysosome, the cargo is degraded, while some metabolic by-products are recycled
and reintroduced in cellular metabolism. Different nutrient-sensing pathways convey signals to

the autophagy machinery by recruiting autophagy-related (ATG) proteins to orchestrate the fine
steps of autophagy development, starting from the biogenesis and maturation of autophagosomes,
up to the fusion with endosomes and lysosomes [48,54,74]. In response to the metabolic needs of
the cells, the concerted actions of the phosphatidylinositol 3-kinase (PI3K)/AKT and the Unc-51 like
autophagy activating kinase-1 (ATG1/ULK1) complexes are key to promote autophagy initiation
through nucleation of phagophores [74]. As a master nutrient sensor, the mammalian target of
rapamycin complex 1 (mTORC1) acts as a primary regulator of autophagy initiation in mammalian
cells through phosphorylation of ATG13 and inhibition of ATG1/ULK1. mTORC1-dependent inhibition
and 5′ AMP-activated Protein Kinase (AMPK)-mediated activation of the ULK1 complex are the
most characterized pathways that couple nutrient sensing to autophagosome biogenesis [48,54,74].
Phosphorylation of the PI3K-III regulatory subunit Beclin-1 (ATG6, BECN1), the formation of the
BECN1/VPS34/ATG14 complex, and phosphorylation of the activating molecule in BECN1-regulated
autophagy (AMBRA1) by ULK1, are equally important in finely tuning the autophagy process from
phagosome biogenesis up to fusion with lysosomes, while balancing autophagy with p38MAPK- and
ERK/JNK-related apoptosis [74]. Conversion of ATG8 [microtubule-associated protein light chain
3 (LC3) in mammals] into soluble LC3I, ubiquitination-like enzymatic lipidation of LC3I to form
lipid-bound LC3II isoform, and finally the incorporation of LC3II into the phagophore membrane are
key steps for the vacuole to expand and seal, thus, allowing the cytoplasmic elements to be properly
engulfed [54].
Along with mTOR- and AMPK-related autophagy, activation of the NAD-dependent deacetylase
Sirtuin-1 (SIRT1) promotes autophagy by de-acetylating different substrates, including ATG5, ATG7,
LC3, as well as transcription factor forkhead box O3 (FOXO3), which transcriptionally up-regulates
several pro-autophagic genes [54,75]. Finally, the transcription factor EB (TFEB) also promotes
autophagy by activating the genes involved in autophagy, autophagosome-lysosome fusion, and
lysosomal biogenesis [48,54,76].
Along with ATG products, specific evolutionary conserved multitasking proteins that regulate
intracellular endosomal/secretory trafficking pathways, such as G-coupled Ras-related proteins in
brain (Rab GTPases) and SNAREs (Soluble N-ethylmaleimide-sensitive factor attachment protein
receptor), are implicated in autophagosome maturation and autophagosome-lysosome fusion [77].
Paradoxically, blockade of lysosomal function can lead to enhanced autophagy initiation via inhibition
of mTORC1 [78]. This might be key to comprehend the effects of SARS-CoV-2 at the level of the
autophagy machinery, as both reduced lysosomal degradation and autophagosome accumulation via
mTOR-ULK1 signaling might facilitate viral replication and transmission (Figure 1) [30,31,78].
In detail, similar to SARS-CoV and MERS-CoV, SARS-CoV-2 is internalized upon the interaction
of spike proteins with ACE2 [79]. Within host cells, the virus is first stored within the endosomal
compartment, from where it releases the viral RNA to initiate replication. Translation and eventually
packaging of mature virions occur within the ER and Golgi apparatus. Many viruses, including
SARS-CoV-2, induce the accumulation of autophagosomes likely to promote their replication
herewith [31,80]. In line with this, many studies have documented an early increase in the number
of double-membrane, autophagy-like vacuoles and endosomes/MVBs, which at first suggested an
abnormal activation of the autophagy pathway, during infection by either influenza viruses or
CoVs [80–84].
Nonetheless, these concepts were recently challenged by accumulating evidence showing that
autophagy compartments are not fully mature, neither do they merge with lysosomes. For instance,
the influenza virus blocks autophagic flux through activation of PI3K/AKT and downregulation of
the autophagosome–lysosome fusion factors Syntaxin-17 (STX17) and V-type proton ATPase subunit
(Figure 1) [85,86]. Autophagy impairment during the influenza virus is due to either NS1 or M2 viral
proteins, and it is associated with enhanced viral protein release and virus-induced apoptotic cell
death [85–87]. Conversely, restoring autophagic flux counteracts these effects [86]. During influenza
virus infection, the non-structural protein NS1 might also impede autophagosome formation through
activation of the PI3K/AKT/mTOR pathway [88]. This is in line with evidence in MERS-CoV-infected
hepatocytes showing an abnormal activation of the PI3K/AKT/mTOR and ERK/MAPK pathways,
which are known to inhibit autophagy [89]. Supporting an impairment of autophagy, pretreatment
with pharmacological inhibitors of these pathways inhibits MERS-CoV infection [89].
Figure 1. Molecular steps of the autophagy pathway and viral-targeted events hampering autophagy
progression. The class I phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin
′
complex 1 (mTORC1), and 5′ AMP-activated Protein Kinase (AMPK) pathways orchestrate autophagy
initiation through regulation of kinase-1 (Atg1/ULK1) and Beclin-1/Vps34/Vps15/Atg14 complexes.
mTORC1 inhibits while AMPK promotes autophagy initiation. The Beclin-1/Vps34/Vps15/Atg14
complex, the NAD-dependent deacetylase Sirtuin-1 (SIRT1), and the transcription factors forkhead
box O3 (FOXO3) and EB (TFEB) promote several steps of the autophagy process, from phagophore
biogenesis up to the fusion of autophagosomes with lysosomes. Various ATG products ranging from
Atg3 to Atg16L are involved in the conversion of LC3 into soluble LC3I, ubiquitination-like enzymatic
lipidation of LC3I to form lipid-bound LC3II isoform, and finally the incorporation of LC3II into the
phagophore membrane, which is a key for the vacuole to expand and seal. Along with ATG products,
specific evolutionarily conserved multitasking proteins that regulate intracellular endosomal/secretory
trafficking pathways, such as Rab11, Rab7, and Syntaxin 17 (STX17), are implicated in autophagosome
maturation and autophagosome–lysosome fusion. The influenza virus blocks autophagic flux through
activation of PI3K/AKT and downregulation of the autophagosome-lysosome fusion factors Syntaxin-17
(STX17) and V-type proton ATPase subunit (V-ATPase). MERS-CoV and SARS-CoV-2 lead to AKT
activation, AMPK inhibition, and subsequent decrease in Beclin-1 and Atg14 levels, underlying the
lack of fusion of autophagosomes with lysosomes. SARS-CoV-2 also downregulates mTOR, which is
likely to enhance the availability of membrane precursors forming autophagy-like vesicles where the
virus replicates.
An impairment of autophagosome formation during influenza virus infection was also associated
with the downregulation of the endocytic protein Rab11a (Figure 1) [88]. In detail, the loss of
the endosomal protein Rab11a impairs the formation of autophagosomes and the engulfment of
viral ribonucleoprotein (vRNP) complexes by autophagosomes in infected cells. This indicates
that Rab11a-positive recycling endosomes, while serving as membrane donors for the phagophore
elongation, also act as a receptor for the engulfment of vRNP complexes within autophagy
compartments [88]. This adds to previous evidence indicating the ER as the major source of
viral-induced autophagosomes, which is documented in the avian bronchitis virus infection [28,83].
Here, the non-structural replicase protein nsp6, which is also present in MERS-CoV and SARS-CoV-2,
contributes to occluding the delivery of viral components to lysosomes, by impairing the expansion
and maturation of ER-derived autophagosomes [28].
A defect in the autophagy flux due to impaired fusion of autophagosomes with lysosomes
is confirmed in SARS-CoV and MERS-CoV, and it was recently documented for SARS-CoV-2
(Figure 1) [30,31,80].
Both MERS-CoV and SARS-CoV-2 infections lead to increased levels of phosphorylated AKT and
subsequent decrease in BECN1 and ATG14 levels, underlying the lack of fusion of autophagosomes
with lysosomes [30,31]. In fact, SARS-CoV-2 downregulates the autophagy-inducing polyamine
spermidine and it occludes AMPK and BECN1-dependent autophagy, while exogenous administration
of either spermidine, AKT inhibitors, and BECN1 stabilizing agents, inhibits SARS-CoV-2 propagation
in vitro [31]. Paradoxically, the virus also induces downregulation of mTOR, indicating that the
SARS-CoV-2-induced autophagy block might be in part independent of mTOR activity, at least during
the early phases of infection. While eventually occluding the conventional autophagy-dependent
degradation of viral contents, which is known as “virophagy/xenophagy”, a non-effective autophagic
flux might also enhance the availability of ER-derived membrane precursors forming autophagy-like
vesicles that are generated during viral replication [31,90]. In this scenario, the early evidence on a
deleterious role of autophagy/endosomal pathway might also be a misinterpretation when focusing on
single autophagy-related genes/proteins or pathways, rather than on the autophagy flux.
At the same time, SARS-CoV-2-induced reduction of mTOR-dependent glycolysis and protein
translation [31] is compatible with the manipulation of the cell cycle or induction of apoptosis, which is
used by many viruses as a strategy to promote their infection cycles [91–94]. This is also documented
for influenza virus and SARS-CoV, which block G1/S phase transition and cell proliferation [91,94].
This occurs mostly through the downregulation of phosphorylated cell cycle regulator retinoblastoma
(Rb), which is placed downstream of specific GTPases, transcription factors, and cyclin-dependent
kinase modulators, such as the Ras homolog gene family member A (RhoA), p53, and p21. Since a
mutual interplay exists between autophagy, UPS, and the above-mentioned [95], it would be worth
investigating whether and how SARS-CoV-2 might exploit such a coordinated response between
cell-clearing systems and cell-cycle arrest.
Autophagy also plays a balancing role intended to ensure a measured anti-inflammatory
response, while avoiding excessive inflammatory tissue damage [41,96]. During viral infection,
viral pathogen-associated molecular patterns (PAMPs) are detected by host cell pattern recognition
receptors (PRRs). PRRs like TLR7 and retinoic acid-inducible gene-I (RIG-I) initiate antiviral responses
by binding of IRAK kinase to MyD88 and phosphorylation of transcriptional factors (NF-kB/AP-1
and IRF3/7). Transcriptional factors promote the generation of IFN-α/β and other pro-inflammatory
cytokines as a first response to the viral infection. Subsequently, IFN-α/β binds to its receptors, inducing
the interferon-stimulated genes (ISGs)-dependent transcription of multiple genes with antiviral effects.
Excessive immune activation and IFN production might cause damage to the body (Figure 2). Host cells
have developed intricate approaches to balance the expression of IFN- α/β, with both proteasomes
and autophagy involved in this regulation [96]. Autophagy can downregulate IFN production by
the degradation of viral PAMPs associated with PRRs (e.g., TLR7) [96,97]. Association of RIG-I with
negative factors leads to its degradation via either p62-mediated autophagy or the proteasome [98–100].
In turn, IFN binding to its receptors can induce the formation of both immunoproteosome and
autophagy (xenophagy), which is involved in the degradation of viral products and induction of
the antiviral state of the IFN-treated cells [96]. An autophagy impairment during CoV infection
might occur along with alterations in IFN-type I signalling, which is key in the early phases of
viral infection [96,101,102]. As shown in MERS-CoV, besides nsp6, the autophagy impairment is
also associated with the non-structural viral proteins 4b and p5 [30], which act as antagonists of
the IFN-type I signaling [103,104]. In influenza virus-infected cells, autophagosome formation and
p62 accumulation witnessing a stall in autophagy progression, are accompanied by limited IFN-β
expression, which might fuel viral replication and spread [105]. On the other hand, the interaction of
viral proteins with BECN1 might contribute to increasing viral replication by hampering fusion of the
autophagosome with the lysosome, meanwhile promoting excessive IFN production [106]. This is
remarkable since CoVs impair BECN1-dependent autophagy flux [30,31], which in turn, is key to
balancing antimicrobial immune responses by promoting xenophagy, while preventing excessive
immune stimulation (Figure 2) [107].
Figure 2. During viral infection, viral pathogen-associated molecular patterns (PAMPs) are detected by
host cell pattern recognition receptors (PRRs). PRRs like TLR7 and retinoic acid-inducible gene-I (RIG-I)
initiate antiviral responses through activation of transcriptional factors NF-kB/AP-1 and IRF3/7. This
promotes the generation of IFN-α/β and other pro-inflammatory cytokines as a first response to the
viral infection. Subsequently, IFN-α/β binds to its receptors, inducing the interferon-stimulated genes
(ISGs)-dependent transcription of multiple genes with antiviral effects. Excessive immune activation
and IFN production might cause damage to α the
β body. In this frame, autophagy is key to balancing
antimicrobial immune responses by inducing α β clearance (xenophagy), CD4+ T-cell-dependent
viral
responses, and immunoglobulin production, meanwhile preventing excessive inflammation and
immune stimulation. By affecting the autophagy machinery, viruses might either hijack the host
immune response or promote excessive immune stimulation and cytokine storm.
The crosstalk between autophagy and IFN-I responses might serve as a major bridge linking
autophagy to innate antiviral immunity, and many viruses can manipulate the key molecules of
the autophagy process to alter IFN-I production [96]. However, a direct link between impairment
of autophagy and IFN signalling remains to be confirmed for CoVs, as most viral proteins are
multifunctional and interact with multiple independent cell processes.
Autophagy is also involved in the processing and (cross)-presentation of antigens on MHC-II
molecules and subsequent activation of CD4+ T-cell-dependent response, while surveilling CD8+
T-cell-dependent cytotoxic response via degradation of MHC-I [41,107]. In addition to T-cell-mediated
immunity, autophagy is also required for in vivo immunoglobulin production and secretion by plasma
cells [108], which might be crucial for the resolution of COVID-19 pathogenesis [109]. On the other
hand, autophagy is key to preventing oxidative damage and excessive inflammation, for instance by
counteracting the COX2-NF-kB-NLRP3 pathways [41,110,111]. Rescuing autophagy might produce

mitigation of oxidative damage and excessive inflammatory response in a variety of tissues and cells
that are known to be affected during COVID-19, including lung epithelial cells, endothelial cells,
cardiomyocytes, neurons, and glia [46,111–115]. In line with this, the belief that autophagy activation
during coronavirus infection might contribute to disease pathogenesis is currently being challenged
by the worsening in the severe respiratory stress upon administration of autophagy/lysosomal
blockers [36,116]. Although such evidence remains contradictory and needs to be confirmed by
rigorous scientific scrutiny, it seems to fit with the pro-inflammatory effects that are produced by either
genetic or pharmacological autophagy blockade [46,117,118].
2.2. Immunoproteasome, Viral Infection, and Inflammation

Viral infections, and pro-inflammatory/oxidative stimuli in general, while potentially altering
autophagy, recruits the immunoproteasome [119]. This represents an alternative, cytokine IFN-γ,
and TNF-α-inducible UPS isoform that owns particular structural features and an increased
chymotrypsin-like catalytic capacity compared to standard proteasomes [120,121]. These features
enable immunoproteasome-dependent processing of either the self or viral antigen peptides and
subsequent activation of CD8+ T-cell-dependent adaptive response via MHC-I presentation at the
plasma membrane [44,119,120].
As a first-line defense, the immunoproteasome is key to counteract viral replication within
the infected cell, though its role appears context- and virus-dependent [119,122,123]. For instance,
contrary to SARS-CoV, MERS-CoV infection in lung epithelial cells induces a massive downregulation
of the host immunoproteasome subunits and MHC genes [122]. Although this was assessed only
at the mRNA levels, which does not necessarily reflect a decrease in immunoproteasome catalytic
activity, this might represent a virus-specific mechanism through which MERS-CoV attempts to hijack
immune activation. This seems compatible with recent evidence that SARS-CoV-2 leads to an mTOR
inhibition, which in turn, is reported to reduce immunoproteasome recruitment, despite increasing
overall UPS-dependent protein degradation [124,125]. Abnormal UPS activity might contribute to
impairing the autophagy machinery. For instance, MERS-CoV infection recruits the E3 ligase SKP2
to impair autophagy progression through the UPS-dependent degradation of BECN1 (Figure 3) [30].
Additionally, the immunoproteasome impairs autophagy through ATG5 and PTEN degradation,
which contributes to exacerbating cardiac hypertrophy in mice models [126,127].
Although immunogenic epitopes in both the structural and non-structural proteins of SARS-CoV-2
that could interact with the MHC-I alleles were identified [128,129], the role of immunoproteasome
in SARS-CoV-2 infection specifically remains to be investigated. While it might be seminal to
elicit an anti-viral adaptive response in the site of infection, it is likely that during the late phases
of infection, when a cytokine storm takes place, the immunoproteasome might be strongly and
persistently recruited to promote an excessive immune reaction fueling autophagy impairment.
This is supported by the fact that immunoproteasome recruitment occurs through activation
of molecular pathways such as PKC, NF-kB, JAK/STAT, AKT/mTOR, ACE/Angiotensin-II/ATR1,
and TLR/RAGEs, which are known to impinge on the autophagy machinery [39,44,48,125–127,130–136].
Additionally, an abnormal persistence of immunoproteasomes might perpetuate excessive inflammation
and immune responses to promote acute respiratory distress, vasculitis, hypertension, myocarditis,
and neuronal damage [44,123,131,132,137–140]. This is associated with abnormal cytotoxic CD8+
T-cell responses also involving neuronal cells, which under excessive pro-inflammatory conditions
upregulate MHC-I molecules, just like antigen-presenting cells [141]. In fact, immunoproteasome
recruitment along with concomitant impairment of autophagy flux is described during inflammation
and oxidative damage occurring in neurodegeneration and neurotoxicity, including that associated with
viral infections [44,142,143]. In this context, autophagy finely-tunes the immunoproteasome-dependent
CD8+ T-cell responses by handling the turnover of MHC-I molecules [107], which suggests
that an autophagy impairment might contribute to exacerbating immunoproteasome-dependent

cytotoxic response.
Figure 3. Abnormal UPS activity might contribute to impairing the autophagy machinery during CoVs
infections through SKP2 recruitment and UPS-dependent degradation of BECN1.
Remarkably, the immunoproteasome-dependent editing and loading of viral antigens on

MHC-I molecules occur in cooperation with the ACE enzyme, which exerts opposite effects to
those of ACE2 [144]. Contrary to ACE2 which degrades angiotensin II (Ang II, vasoconstrictor)
to angiotensin 1–7 (vasodilator), ACE promotes the synthesis of Ang II while adding to the
immunoproteasome-dependent generation of MHC-I peptides [144]. Ang II, while acting as
a vasoconstrictor through the AT1 receptor (AT1R), promotes immunoproteasome activation in
various experimental models [131,132,145–148]. The synergistic interaction between ACE, Ang-II,
and the immunoproteasome might be key, since, despite ACE2 fostering intracellular SARS-CoV-2
entry, the endocytic internalization of ACE2-SARS-CoV-2 complexes might reduce the amount of
ACE2 available on the membrane surface, leading to vasoconstriction [149,150]. This is bound to
abnormal activation of the Ang-II/AT1R axis, which recruits the immunoproteasome, and occludes
the protective effects of ACE2 against acute lung injury, cardiovascular damage, and neurogenic
hypertension [131,132,145–148,150,151]. Remarkably, while autophagy inhibition might exacerbate
the effects of ACE2 loss- and Ang II-induced pro-inflammatory responses and mitochondrial
alterations [130,152,153], immunoproteasome inhibition rescues autophagy and ameliorates Ang
II-related hypertension, cardiac hypertrophy, and myocarditis [126,131,132,145–148,154]. These pieces
of evidence support the opposite role of autophagy and immunoproteasome in COVID-19-related
multisystem complications, which remains to be experimentally confirmed (Figure 4).
Figure 4. ACE2 degrades angiotensin II (Ang II, vasoconstrictor) to angiotensin 1–7 (Ang-1-7,
vasodilator), while ACE promotes the synthesis of Ang II. Increased levels of Ang II occur following
ACE2-SARS-CoV-2 binding and ACE2 endocytic internalization. This leads to a reduction of ACE2
available on the membrane surface and abnormal activation of the Ang-II/AT1R axis, which occludes
the protective effects of ACE2, thus, promoting vasoconstriction, fibrosis, inflammation, mitochondrial
damage, and apoptosis, meanwhile recruiting the immunoproteasome, and impairing autophagy.
2.3. Autophagy Impairment, Exosome Release, and Inflammation

Autophagy impairment is known to trigger unconventional pathways aimed at getting rid of
overwhelming intracellular cargoes through the release of either free or exosome-engulfed material [151].
Exosomes derive from intraluminal vesicles that are generated in the MVB compartment, following late
endosomal membrane inward budding. MVBs can either fuse with autophagosomes and lysosomes
where cargo degradation eventually occurs, or can fuse with the plasma membrane to release exosomes
into the extracellular space [155]. On the one hand, this might be considered as a natural mechanism
that cells have preserved to communicate with each other and share essential cell constituents within
a common environment. On the other hand, when suppression of autophagosome maturation or
fusion with the lysosome occurs, inadequate digestion of intracellular cargoes might promote the
exosomal release of potentially deleterious material [48,155]. Thus, promoting autophagy flux through
the fusion of MVBs with autophagosomes and lysosomes might reduce exosome biogenesis and
secretion [48,142,156,157].
This is crucial since the intrapulmonary spreading of respiratory viruses, including CoVs, might
occur through exosomes containing viral particles and also the proteasome subunits, which might spread
either closely or at distant sites through the blood-stream or body fluids [156,157]. Thus, the spreading of
SARS-CoV-2 particles might further occlude the autophagy machinery to produce severe inflammation
in the wall of blood vessels, leading to vasculitis, which mainly affects highly perfused organs. This is
supported by evidence showing that autophagy impairment might increase vascular inflammation,
platelet aggregation, and atherosclerosis, which can be healed by autophagy activation [68,158].
Again, activation of autophagy is a beneficial process during cardiovascular damage induced by
mechanical overload, ischemia, and oxidative stress in various animal models, where it ensures the
preservation of ATP content and degradation of damaged mitochondria [45,133,159–162]. Autophagy
activation is also beneficial in models of metabolic syndrome and diabetes [161,163], which are
frequently associated with atherosclerosis and ischemic heart disease and represent an important risk
factor for developing severe and critical forms of COVID-19 [164].
Exosome-based virus spreading might also recruit peripheral nerves as a gateway to enter the CNS.
Such involvement might go beyond neuro-vasculitis to recruit in a site-specific fashion those nuclei
that receive projection from viral-exposed organs. As reported for SARS-CoV, the vagal innervation of
the lung might spread the virus within cardiorespiratory target nuclei of the brainstem [25], such as
the dorsal vagal nucleus, the ala cinerea, the area postrema forming the dorsal respiratory group,
as well as the interconnected ventral respiratory group where the pre-Boetzinger complex is placed.
This engagement is consistent with the high expression of ACE2 mRNA and protein levels in the
nucleus of tractus solitarius/dorsal motor nucleus of the vagus and the ventrolateral medulla [27].
ACE2 expression in brain areas involved in the control of cardiovascular function suggests that the
carboxypeptidase might play a role in the central regulation of blood pressure and diseases involving the
autonomic nervous system, such as hypertension. This might explain the abnormal cardiorespiratory
activity adding to the peripheral involvement of the blood vessels in the lung and the heart, eventually
contributing to cardiopulmonary fatalities occurring in COVID-19. Similarly, olfactory-related brain
structures might be recruited when the virus progresses through the olfactory nerve to infect and
promote the degeneration of neurons in the olfactory bulb and piriform cortex, as documented in
SARS-CoV-infected mice expressing the receptor ACE2 [25]. Such a phenomenon might explain the
typical anosmia that is documented in COVID-19 patients [165].
The extracellular spreading of the virus following impairment of autophagy–lysosome fusion is
compatible with the trans-cellular diffusion of microvesicles that takes place in the CNS, to communicate
physiological signals or spread disease through danger-associated molecular pathways (DAMPs).
In fact, besides cell lysis, an autophagy impairment in virus-infected cells might promote the
extracellular release of undigested, vesicular-packed DAMPs such as HMGB1 [166–168]. Once released
extracellularly, HMGB1 initiates inflammation in either neighbor or distant host cells, via the activation
of TLR4 and RAGE receptors, fuelling NLRP inflammasome activation and pro-inflammatory cytokine
release [166,167]. These events might converge on further immunoproteasome recruitment and
autophagy impairment in different kinds of cells, eventually promoting systemic inflammation
and immune-mediated cytotoxicity [41,110,111,133–136,166]. This substantiates the hypothesis that
excessive immunoproteasome recruitment going along with an autophagy impairment might contribute
to sustaining the multisystem COVID-19 pathogenesis (Figure 5). Such a hypothesis is further supported
by experimental evidence showing that the downregulation of immunoproteasomes, through activation
of autophagy-related pathways, does counteract sepsis in animal models [69]. Additionally, this is
supported by evidence from COVID-19 patients when focusing on CD8+ and CD4+ T-cell responses,
which are bound to immunoproteasome- and autophagy-dependent antigen presentation, respectively.
In fact, higher levels of CD8+ T-cells are detected in COVID-19 patients compared with controls, and a
dramatic reduction of CD4+ T helper cells occurs in the most severe rather than mild COVID-19
cases [169].
Altogether, these pieces of evidence suggest that enhancing autophagy along with blunting
immunoproteasome activity might be beneficial against excessive inflammatory conditions. In search
of natural-based, potentially safe autophagy/(immuno-)proteasome modulators, in the following
sections, we focus on some selected nutraceutical compounds that are known to provide antiviral
and anti-inflammatory effects in the frame of respiratory, cardiovascular, and neuronal alterations,
which might be relevant for COVID-19 multisystem pathogenesis.
Figure 5. Summary of the potential mechanisms underlying SARS-CoV-2-induced alterations of

autophagy and (immuno-)proteasome. SARS-CoV-2 is internalized within host cells (left side of the
cartoon) upon the interaction of spike proteins with ACE2 and is first stored within the endosomal
compartment. From here it releases the viral RNA upon membrane fusion to initiate the viral
replication. Translation and eventual packaging of mature virions occur within the ER and Golgi
(not shown). While increasing the number of autophagosomes to replicate herewith, SARS-CoV-2
blocks their fusion with lysosomes through a proteasome-dependent mechanism. This is likely
due to the standard proteasome (SP) since immunoproteasome (IP) might be hijacked by the virus
to avoid activation of the adaptive immune response. Impairment of autophagy flux eventually
occludes the degradation of virions and viral components, while promoting their propagation from
cell-to-cell, via exocytosis. Once released extracellularly, exosomes containing indigested viruses
and viral material can reach distant tissues, besides neighboring cells (right side of the cartoon).
SARS-CoV-2 also leads to ACE2 downregulation via AngII/AT1R-dependent internalization and
lysosomal digestion. At the same time, a cascade of intracellular events (Ang-II-ATR1, PKC, NF-kB,
JAK/STAT, AKT/AMPK/mTOR, NLRP/HMBG1) takes place to promote pro-inflammatory/oxidative
events, while recruiting the immunoproteasome. These same events exacerbate the autophagy failure,
which is induced by SARS-CoV-2, eventually promoting the extracellular release of virions and DAMPs
along with activation of immunoproteasome-depended cytotoxic CD8+ T-cell response. In this way,
DAMPs and cytokines further alter cell-clearing systems within host cells via binding to RAGEs, TLR4,
and IFN receptors, while promoting systemic inflammation.
3. Anti-Viral and Anti-Inflammatory Effects of Phytochemicals: Is There a Role for Cell-Clearing Systems?
In the context of COVID-19, phytochemical formulations and flavonoids from THM are now
actively employed as an adjunct strategy to antiviral drugs [56,59,60,67]. Some encouraging results
emerged for THM formulas that are rich in resveratrol, quercetin, and kaempferol [56,59,60,63,66].
This is documented in experimental models and patients affected by either sterile lung injury or
respiratory viral infections, including SARS-CoV-2 [56,59,60,63,65,66]. This is also supported by
network-based studies that identified resveratrol, quercetin, and kaempferol as “hub” components
of THM formulas being employed in human respiratory viral infections, including influenza virus
and SARS-CoV-2 [62,64]. These specific phytochemicals are predicted to exert the most effective
pharmacological activity against influenza virus and SARS-CoV-2, by synergistically intervening in
key pathways that are implicated in both viral replication and virus-induced inflammation, chemokine
production, vascular permeability, and oxidative stress-induced apoptosis [62,64]. Similar mechanisms
of action are reported for other less known, though potentially beneficial THM phytochemicals such
as baicalein/baicalin, and cordycepin [57,61]. The list of nutraceuticals and herbal compounds that
possess potential antiviral and anti-inflammatory activity is much longer. Here, we chose as an example
only a few, specific, naturally-occurring compounds, to discuss evidence linking their mechanisms
of action with autophagy and the (immuno)-proteasome. This might be relevant for various steps of
SARS-CoV-2 infection, where autophagy and immunoproteasome are involved, ranging from viral
replication to inflammation-related multisystem pathogenesis.
3.1. Resveratrol
As widely documented in the literature, the stilbene resveratrol induces autophagy and
promotes autophagy flux through either AMPK/SIRT1 or TFEB activation, or PI3K/AKT/mTORC1/2
inhibition [68,161,162,170–177]. Besides induction of autophagy proteins such as LC3II, BECN1,
Rab7, and ATG16L, potentiation of autophagy flux induced by resveratrol is evident by the
enhanced clearance of autophagy–lysosomal substrates, including p62 and intracellular pathogens,
and it is confirmed by the administration of autophagy/lysosome inhibitors, which indeed
occlude the beneficial effects of resveratrol [68,161,170–177]. Resveratrol-induced autophagy
is associated with anti-inflammatory, anti-oxidant, and anti-apoptotic effects in a variety of
inflammatory-related conditions, including bacterial infection, sepsis, acute lung injury, platelet
aggregation, pulmonary thrombosis, hypertension, vascular endothelial inflammation, myocardial
and hepatic injury, arthritis, subarachnoid hemorrhage-induced neuronal injury, and toxicant-induced
neuroinflammation [68,161,162,170–177]. Resveratrol-induced autophagy is also associated with the
rescue of Nrf2, which is involved in mitophagy (the selective removal of senescent/dysfunctional
mitochondria by autophagy) and mitochondrial biogenesis, protection from oxidative stress,
and caspase-dependent apoptosis, as well as downregulation of the HMGB1/TLR4/MyD88/NF-κB
pathway, NLRP3 inflammasome, and pro-inflammatory cytokines production [68,171–177].
Remarkably, resveratrol also blunts immunoproteasome activation, and this is associated
with autophagy induction and protective effects in the experimental models of sepsis and
cardiac hypertrophy [69,127]. In detail, resveratrol, through immunoproteasome downregulation,
prevents immunoproteasome-dependent PTEN degradation to foster autophagy induction in vivo,
while inhibiting the expression of NF-kB, NLRP inflammasome, and pro-inflammatory cytokines
in vitro [69,127]. As shown in the LPS-treated monocytes and cells of sepsis patients, resveratrol acts
mainly through downregulation of the LMP7 (B5i) immunoproteasome subunit, which is responsible
for its enhanced chymotrypsin-like activity [69]. The efficacy of resveratrol is comparable to that of the
selective LMP7 inhibitor ONX-0914, though its effects on immunoproteasome inhibition are milder
and occur in the absence of toxicity, as compared to ONX-0914.
Resveratrol also possesses anti-viral effects, though direct evidence linking cell-clearing pathways
with the anti-viral effects of resveratrol is missing so far. However, resveratrol, either in vitro or in vivo,
counteracts replication of the influenza virus, SARS-CoV, or MERS-CoV, through inhibition of the
p38MAPK and PI3K/AKT/mTOR pathways, which are involved in autophagy impairment, besides
virus-induced apoptosis and inflammation [89,178–181]. The in vivo and in vitro anti-influenza viral
effects of resveratrol are already achieved at low, non-toxic concentrations of 1 mg/kg/day for 7 days
and 62.5 µM, respectively [179,181]. The antiviral efficacy of resveratrol is reduced when the cells are
treated with neutralizing anti-IFN-β antibodies, suggesting that it acts synergistically with IFN-β,
to inhibit influenza virus replication, while promoting the activation of the host immune response [180].
Noteworthy, a recent study indicated a key role for resveratrol against the SARS-CoV-2 spike
protein and human ACE2 receptor complex affinity and stability [182]. By using molecular dynamics
simulation and binding free energy analysis based on molecular docking, resveratrol was found to
rank first among those compounds showing the best affinity for spike protein—the ACE2 receptor
complex. Thus, resveratrol holds potential as an anti-COVID-19 drug candidate, by acting through
disruption of the spike protein—the ACE2 complex [182].
Some recent papers discussed evidence that resveratrol might provide beneficial multisystem
effects in COVID-19 pathogenesis by rescuing downregulation of ACE2 and counteracting Ang II
increase, which is expected to occur following viral infection [183,184]. This is associated with
SIRT1-dependent downregulation of AT1R and Ang II levels [183,184]. In line with this, resveratrol also
counteracts downstream events that are synergistically induced by Ang II and TNF-α in experimental
acute pulmonary thromboembolism and pulmonary artery hypertension, including activation of
p38MAPK, NF-kB, and monocyte chemoattractant protein-1 (MCP-1) [185,186]. Given the links
among resveratrol, cell-clearing systems, and Ang II, it might be inferred that these effects are closely
related to autophagy activation and immunoproteasome downregulation. However, this appears
paradoxical when considering that ACE2 downregulation following SARS-CoV infection is bound
to AT1R-induced ACE2 internalization and degradation into lysosomes, which does not support a
beneficial role for autophagy inducers [147]. However, resveratrol might act at an earlier step of ACE2
internalization, either by blocking the SARS-CoV-2-spike protein—ACE2 receptor complex [182] or
through Ang II-AT1R downregulation. This is expected to prevent ACE2 translocation to lysosomes
while preserving both ACE2 and the autophagy activity. At the same time, resveratrol, through
Ang II-AT1R downregulation, is supposed to blunt Ang II-related complications that are bound to
immunoproteasome hyper-activation.
In line with this, resveratrol protects against experimental ALI, pulmonary embolism-induced
cardiac injury, as well as cerebrovascular and neuronal inflammation, by mitigating signaling pathways
that occur during viral infection and which are bound to a concomitant immunoproteasome activation
and autophagy impairment, including RAGEs, HMGB1, TLR4, NF-kB, and NLRP3 [161,176,177,187,188].
Resveratrol-related inhibition of neuro-inflammation goes along with microglia polarization towards
the anti-inflammatory M2 phenotype and it occurs through SIRT1 and PGC-1α activation [189,190],
which are both bound to autophagy stimulation.
While experimental studies appear necessary to investigate whether these events occur in
SARS-CoV-2, the evidence discussed here supports the hypothesis that resveratrol might play an
active role against key events characterizing multisystem COVID-19 pathogenesis, at least in part,
by targeting alterations in autophagy and immunoproteasome pathways.
3.2. Quercetin and Kaempferol

Both quercetin and kaempferol, two natural flavonoids, were shown to produce anti-inflammatory
effects through autophagy induction [70,71,191,192]. In a mice model of severe progressive pulmonary
fibrosis, kaempferol significantly inhibits pulmonary inflammation and inflammatory cells infiltration,
through the restoration of LC3 lipidation and a concomitant increase in autophagy flux. In fact, blocking
autophagy flux through autophagy/lysosome inhibitors antagonizes the anti-inflammatory effects of
kaempferol during pulmonary fibrosis [70]. Again, kaempferol counteracts in vivo neuroinflammation
and provides neuroprotection, by inhibiting NLRP3 inflammasome activation and IL-1β secretion [191].
These effects are associated with a rescue of autophagy and potentiation of autophagy flux in microglia,
and subsequent degradation of ubiquitinated NLRP3, which is prevented by either ATG5 knockdown
or treatment with autophagy/lysosome inhibitors [191].
Similarly, quercetin and its O-glycoside quercitrin are both able to induce autophagy producing
anti-oxidant and anti-inflammatory effects, which are abolished by pharmacological autophagy
inhibition in animal models of atherosclerosis [71,192]. Quercetin induces autophagy through mTOR
inhibition, which is associated with an improvement of aortic ultrastructural morphology and decreased
levels of TNF-α, IL-1β, IL-18 [71]. Quercetin, through autophagy induction, also inhibits NLRP3
activation while protecting mitochondrial integrity and inhibiting ROS production, upon bacterial
infection in vitro [193]. Similar to resveratrol, quercetin activates the autophagy-related AMPK/SIRT1
axis to counteract HSV-1 neuro-infection, propagation, and subsequent increases in neuropathological
protein aggregates [194]. As the main constituents of a hydroalcoholic extract from Fragaria vesca leaves,
quercetin and kaempferol produce nitric oxide scavenging and anti-inflammatory activity in LPS-treated
macrophages, which is associated with proteasome inhibition and autophagy induction [195].
This is in line with several studies suggesting that both quercetin and kaempferol, especially in
their glycosylated forms, produce beneficial effects in a variety of conditions that might be relevant for
COVID-19 multisystem pathogenesis, including lung inflammation and pulmonary fibrosis, coronary
heart disease, myocardial infarction, diabetes, and neuroinflammation [70,196–199]. These effects are
associated with a reduction of blood pressure, and inhibition of pro-inflammatory cytokine release,
platelet aggregation, and ACE-Ang-II [198,199]. Neuroprotective effects of quercetin and kaempferol
are widely documented in various experimental models, which are associated, either directly or
indirectly, with modulation of autophagy and immunoproteasome pathways. These include reduction
of oxidative stress and neuroinflammation, induction of M2 microglia polarization, improvement
of BBB function, prevention of AGE/RAGE-related neuronal damage, inhibition of HMBG1/TLR4
axis, and activation of AMPK and Nrf2 [200–206]. Both quercetin and kaempferol, through inhibition
of cytochrome P-450-dependent catalysis, prevent the hepatic metabolism of 17 beta-estradiol [207],
whose effects are bound to autophagy activity [208] and are potentially relevant in the frame of either
influenza virus or COVID-19 pathogenesis [209,210].
Remarkably, both quercetin and kaempferol possess anti-viral activity, although associations with
cell-clearing systems are poorly investigated. Quercetin and kaempferol are among the most active
antiviral components of Aloe vera, which effectively reduces the viral replication of the influenza virus
in vitro, which is bound to the inhibition of autophagy [211]. In line with the binding affinity of quercetin
and kaempferol for the M2 protein of the influenza virus, quercetin- and kaempferol derivatives
were also identified as potential inhibitors of the 3C-like protease (3CL(pro)) of SARS-CoV [212] and
SARS-CoV-2 [213]. Recent molecular binding studies suggest that both quercetin and kaempferol can
block the interaction sites on the SARS-CoV-2 spike—ACE2 [214,215]. Quercetin and its derivatives
quercetin-3-rhamnoside and isoquercetin, effectively inhibit the replication of the influenza virus
both in vitro and in vivo [216–218]. In vitro, quercetin-3-rhamnoside inhibits the influenza virus
replication with a higher efficiency, as compared with oseltamivir, though such an antiviral effect is
potentiated when either quercetin, quercetin-3-rhamnoside, or isoquercetin are co-administered with
oseltamivir [216,218]. Compared to other polyphenols that exert antiviral activity in vitro, isoquercetin
shows the lowest values for the effective dose, for a 50% reduction on viral replication (ED50) and
toxic dose for 50% cell death (TD50), namely 1.2 uM and 46 uM, respectively. During influenza
virus infection, isoquercetin pre-administration at either 2 or 10 mg/kg/day decreases the influenza
virus titers, pro-inflammatory markers, and pathological changes in the lung of infected mice [217].
Similar effects occur following pre-treatment with quercetin 20 mg/kg b.w., which reduces oxidative
damage in the lungs and liver of infected mice [219]. In summary, quercetin and kaempferol counteract
the replication of respiratory viruses and protect against viral-induced apoptosis, which warrants
further studies investigating their potential efficacy in SARS-CoV-2 infection. This is also supported by
the widespread, anti-inflammatory, and autophagy-related effects of quercetin and kaempferol in a

variety of conditions that might be relevant for multisystem COVID-19 pathogenesis.
3.3. Cordycepin
Pioneering studies of the late 1970s’ showed that cordycepin, the main bioactive compound of
the Cordyceps mushroom genus, selectively inhibits the replication of the influenza virus by occluding
the intracellular viral RNA synthesis [220,221]. Since then, there is a paucity of studies on the effects
of cordycepin against respiratory viruses, despite several ones documenting its antiviral activity in
human immunodeficiency virus (HIV), murine leukemia virus, and Epstein-Barr virus (EBV) [222].
Nonetheless, cordycepin is widely used in the THM for the treatment of respiratory diseases and
it appears beneficial in human lung diseases [57]. This is confirmed in animal models of chronic
obstructive pulmonary disease, where cordycepin improves tissue morphological changes such as
thinning of the airway walls, infiltration of inflammatory cells, and sub-epithelial fibrosis [223]. It also
reduces the accumulation of macrophages, neutrophils, and lymphocytes in the bronchoalveolar fluid,
while downregulating the inflammatory cytokines TNF-α, IL-8, TGF-β1 [223]. Similar effects are
recapitulated through in vitro and in vivo in models of pulmonary inflammation and lung fibrosis,
where cordycepin suppresses IL-1β and IL-18 secretion through inhibition of NLRP3 inflammasome,
both in human-derived macrophages and in mice lung tissues [224,225]. At the same time, cordycepin
restores superoxide dismutase (SOD) expression, while inhibiting ROS production in TGF-β1–treated
lung fibroblasts and epithelial cells [225]. In LPS-activated macrophages and experimental ALI mice,
cordycepin inhibits NF-kB, while reducing the expression of COX2, TNF-α, IL-6, and IL-1β [226,227].
This is associated with protection against alveolar epithelium damage and edema, and reduced
infiltration of inflammatory cells in the bronchoalveolar fluid of ALI mice [227]. Remarkably, cordycepin
was shown to induce autophagy and promote autophagy flux, as evident by the upregulation of BECN1
and LC3-II and downregulation of p62, which is associated with beneficial effects in experimental
mice of diabetic nephropathy [72]. While reversing histopathological injuries in the kidney of diseased
mice, cordycepin suppresses inflammation, apoptosis, and renal fibrosis by decreasing IL-1β, IL-6,
and IL-18, as well as TUNEL staining, and the expression of fibrosis markers [72]. All these effects are
abolished by the autophagy inhibitor 3-MA [72]. This is recapitulated in salt-sensitive rats that are
fed via a high-salt diet, where cordycepin-induced autophagy is associated with lifespan extension
and protection of hypertension-sensitive organs, including the brain, heart, kidney, and liver [228].
Morphologically, neurons, cardiomyocytes, glomerular podocytes, renal epithelial cells, and hepatocytes
are all improved in cordycepin-treated rats featuring reduced levels of AKT/mTOR, increased levels
of AMPK, and decreased levels of p62 witnessing for autophagy flux progression, as compared to
the untreated controls [228]. A cordycepin derivative, through AMPK activation, also alleviates
atherosclerosis in High-Fat Diet-Fed ApoE-KO mice, by protecting the vascular endothelial cells
from inflammatory and oxidative damage [229]. Thus, cordycepin might be a potential modulator of
autophagy to be tested in the frame of SARS-CoV-2 infection.
3.4. Baicalein and Baicalin

The two major flavonoids of Scutellaria baicalensis, baicalein and its aglycone metabolite baicalin,
possess widespread biological activities, including anti-bacterial, anti-viral, anti-inflammatory,
anti-oxidant, neurotrophic, and neuroprotective effects [67,230]. Baicalein and baicalin show
inhibitory effects on various strains of influenza virus and SARS-CoV, both in vitro and in vivo.
Oral administration of baicalein to mice infected with the influenza virus increases the mean time to
death, inhibits lung inflammation, and reduces the lung virus titer in a dose-dependent manner [231].
These effects are likely due to baicalin, the metabolite of baicalein, which was shown to inhibit
both influenza virus and SARS-CoV replication in vitro [231,232]. In detail, baicalin showed in vitro
antiviral activity against nine strains of SARS-CoV collected from patients’ lung tissue biopsy, urine,
and nasopharyngeal aspirates [232]. The inhibitory effects of baicalin are similar to those of leukocytic
IFN-α, IFN-β-1a, ribavirin, lopinavir, and rimantadine, though some differences in terms of efficacy are
observed, depending on the cell lines employed [232]. The range of the effective concentration of baicalin
required to reduce the plaque-forming unit (cytopathic effect) by 50% (EC50) was estimated as 11 µg/mL,
and the cytotoxic concentration that reduced cell viability to 50% (CC50) was >100 µg/mL [232].
Baicalin was shown to inhibit influenza virus replication through TRAF6-dependent expression
of Type-I IFNs, which correlated with protection against ALI in infected mice [233]. This is interesting
since, in SARS-CoV, similar to what was observed in the influenza virus, inhibition of TRAF6-dependent
expression of Type-I IFNs was associated with an abnormal UPS-dependent degradation, eventually
leading to alterations in mitochondrial homeostasis and autophagy [234]. This fits with evidence
documenting an inhibitory effect of baicalin on the chymotrypsin-like activity of the proteasome [73].
Remarkably, baicalin, sodium baicalin, and baicalein counteract the influenza virus infection, both
in vitro and in vivo, by directly inhibiting the neuraminidase surface glycoprotein that is necessary
for viral replication and the release of virions from infected cells [235,236]. Sodium baicalin is also
effective against oseltamivir-resistant mutant influenza virus strains [236] while baicalein enhances
the anti-viral effects of the neuraminidase inhibitor zanamivir [237]. The anti-neuraminidase activity
of baicalein is accompanied by a downregulation of TNF-α, IL-6, and IL-8, which is associated with
inhibition of the NF-kB and PI3K/AKT pathways, suggesting a potential activation of autophagy [237].
This is in contrast to studies associating the antiviral activity of baicalin with an attenuation of influenza
virus-induced autophagy [238]. Such controversy might be related to either a viral-strain specificity or
to the same paradoxical mTOR-related effects that are observed during SARS-CoV-2 infection [31].
Nevertheless, this calls for considering potential misinterpretations of the autophagy status since
influenza virus was confirmed to block autophagy–lysosome fusion similar to CoVs [86]. This also
fits with evidence showing that baicalin directly targets the NS1 protein of the influenza virus [239],
which is shown to impair autophagy through PI3K/AKT activation [85,88]. Remarkably, baicalein can
bind the N-terminus and C-terminus of the homology model of the SARS-CoV-2 proteins Nsp14 and
3CLpro, providing a potential candidate drug against SARS-CoV-2, for further study [240,241].
In addition to viral infections, baicalin and baicalein produce antioxidant and anti-inflammatory
effects in several experimental inflammatory conditions, including diabetes, atherosclerosis,
cardiovascular diseases, inflammatory bowel disease, rheumatoid arthritis, as well as liver-, kidney-,
psychiatric- and neurodegenerative- diseases [67,242,243]. This is largely bound to key molecular
pathways being implicated in the same antiviral activity of these compounds, namely attenuation of
the NF-kB pathway and pro-inflammatory cytokines and chemokines such as TNF-α, IL-6 and IL-8,
and MCP-1, ROS scavenging, and improvement of antioxidant status, as well as inhibition of COX2 and
lipoxygenases [243]. The anti-inflammatory and anti-apoptotic effects of baicalin/baicalin are also bound
to autophagy stimulation. In a model of arthritis consisting of IL-1β-treated chondrocytes, baicalin
rescues autophagy to confer protection through the up-regulation of BECN1 and LC3 II/LC3 I ratio, and
potentiation of autophagy flux, as evident by the decreased p62 levels [244]. In experimental models of
hyperglycemia-induced myocardial damage, autophagy flux inhibitors occlude the anti-oxidant and
anti-apoptotic effects of baicalin [245]. These findings are in line with evidence on baicalein acting as
an inducer of autophagy flux, as documented by luciferase-based reporter assays [246].
Thus, baicalin and baicalein represent potential modulators of cell-clearing systems that deserve
to be investigated in the frame of the multisystem COVID-19 pathogenesis. A summary of the
anti-inflammatory, anti-viral, anti-apoptotic, and cell-clearing-related effects of phytochemicals
discussed so far is provided in Table 1.
Table 1. Summary of the anti-inflammatory, anti-viral, anti-apoptotic, and cell-clearing-related effects of phytochemicals.
Phytochemical Autophagy-Related Effects UPS-Related Effects Anti-Inflammatory Anti-Viral Anti-Apoptotic

and Experimental Model Effects Effects Effects
Resveratrol
TNF-α-induced endothelial ↑LC3II/LC3I ratio ↑BECN1 ↓LMP7, LMP2 ↓ICAM-1 ↓NF-κB Influenza virus ↓caspase-3/9/12
inflammation, and ↑Rab7 immunoproteasome ↓IL-1β, IL-6, IL-8 [179,180] ↓BAX/Bcl-2
endothelial oxidative injury ↑ATG16L1 [69,127] ↓TNF-α ↓IFN-γ MERS-CoV [181] ↓TUNEL
[68,171,247] ↑PTEN ↓iNOS ↓COX-2 ↓ACE2-SARS-CoV-2 S ↓p-p38 MPAK
LPS-treated monocytes and microglia ↑SIRT1/AMPK ↑TFEB ↓NLRP3 ↓MCP-1 protein binding [182] [127,129,185,186,188,248]
[69,190] ↑flux ↓p62 ↓TLR4/MyD88/NF-κB HSV-1 [194]
Cardiac hypertrophy/ ↑xenophagy ↓HMBG1 release
Ang-II-treated cardiomyocytes [127] [68,127,161,170,171,173–176, ↓RAGE/MAPK/
Diabetic cardiomyopathy [161] 247,248] NF-κB
Intracellular bacterial infection [170] [68,69,170,171,173,175–177,
Monocytes from chronic kidney disease 185,186,188,190]
(CKD) patients [173]
Pulmonary thrombosis, pulmonary
artery hypertension, and platelet
aggregation
[174,185,186]
Subarachnoid hemorrhage,
hypoxic/ischemia brain injury, and spinal
cord injury
[175,177,248]
Plasma cells from gout patients [176]
AGEs-induced inflammation [188]
Quercetin and derivatives
Pulmonary fibrosis [70] ↑LC3II/LC3I ratio ↑BECN1 ↓Chymotrypsin-like ↓IL-1β, IL-6, IL-8, IL-18 Herpes simplex virus type-1 ↓caspase-3
Oxidized low-density lipoprotein-treated ↓Akt activity [195] ↓TNF-α ↓NLRP3 (HSV-1) [194] ↓BAX/Bcl-2
endothelial cells [192] ↑AMPK/Sirt1 ↓iNOS ↓COX-2 Influenza virus ↓TUNEL
Intracellular bacterial infection [193] ↑flux ↓STAT1/NF-κB [211,216–219] [192]
Viral neuro-infection [194] [70,192–195] [70,193,195,196,204,205] ↑Interaction on SARS-CoV-2
LPS-triggered macrophages [195] and SARS-CoV proteins
Lung hypoxia [196] [212–214]
LPS-induced neuroinflammation [204] ↓ACE2-SARS-CoV-2 S
Spinal cord injury [205] protein binding [215]
Table 1. Cont.
Phytochemical Autophagy-Related Effects UPS-Related Effects Anti-Inflammatory Anti-Viral Anti-Apoptotic

and Experimental Model Effects Effects Effects
Kaempferol
Atherosclerosis [71] ↑LC3II/LC3I ratio ↓Chymotrypsin-like ↓IL-1β, IL-18, IL-6, IL-8 Influenza virus [211] ↓caspase-1
LPS-triggered macrophages [195] ↑flux activity [195] ↓TNF-α ↓NLRP3 ↑Interaction on SARS-CoV-2 [191]
LPS-, IFN-γ-, and SNCA-induced ↑AMPK/Nrf2 ↓iNOS ↓COX-2 proteins [214]
neuroinflammation and [71,191,195,201] ↓MCP-2 ↓ACE2-SARS-CoV-2 S
neurodegeneration [191,200,201,203] ↓TLR4/MyD88/NF-κB protein binding [215]
↓HMBG1 release
[71,191,195,200,201,203]
Cordycepin
Diabetic nephropathy [72] ↑LC3II/LC3I ratio - ↓TNF-α ↓TGF-β Influenza virus ↓caspase-3
Chronic obstructive pulmonary disease, ↑BECN1 ↓ IL-1β, Il-6, IL-8, IL-18 [220] ↓BAX/Bcl-2
pulmonary inflammation, and fibrosis ↑flux ↓p62 ↓NLRP3 ↓NF-κB Epstein-Barr virus [222] ↓TUNEL
[223–225] ↑AMPK ↓iNOS ↓COX-2 [72]
LPS-triggered macrophages [226] ↑Cathepsin D [72,223–227,229]
LPS-induced acute lung injury [227] ↑mitochondrial
Hypertension-induced multi-organ function/mitophagy
damage [228] [72,228,229]
Atherosclerosis [229]
Baicalin/baicalein
High glucose-induced vascular ↑LC3II/LC3I ratio ↓Chymotrypsin-like ↑Type I IFN [231] Influenza virus ↓caspase-3
inflammation [242] ↑BECN1 activity [73] ↓ICAM-1 ↓NF-κB [231,233,235–239] ↓BAX/Bcl-2
Arthritis [243] ↑flux ↓p62 ↓IL-8 ↓MCP-1 SARS-CoV [232] ↓PI staining and flow
Hyperglycemia-induced cardiovascular ↓PI3K/AKT [237,242] ↑Interaction on SARS-CoV-2 cytometry
alterations [244] [237,244,245] proteins [243,244]
[240,241]
4. Conclusions
The current understanding of COVID-19 pathogenesis suggests uncontrolled host immune
response and cytokine storm, though randomized trials providing evidence for any effective therapies
against the disease are still lacking [249,250]. The absence of evidence-based medicine and approved
drugs has shifted the focus on clinical insights and patient management through collaborative efforts
in hospitals around the globe [249]. In the present review, we discussed evidence supporting the
hypothesis that COVID-19 multisystem pathogenesis is bound to alterations of cell-clearing pathways
within a variety of potentially affected tissues, including lungs, blood vessels, heart, and brain.
The molecular hypothesis is grounded on data showing how viral particles within infected cells
are entrapped within abundant autophagy-like vacuoles, which are actually impaired to merge
with the lysosomes, thus, altering the clearance of the virus itself. Coupled with the spreading of
pro-inflammatory reactions, this leads to a further autophagy impairment, while persistently recruiting
the immunoproteasome. These events converge in spreading the virus to neighboring and distant
sites on the one hand, while perpetuating systemic pro-inflammatory and cytotoxic immune reactions,
on the other. Despite the significance of such an alteration still being unclear in the context of COVID-19,
it seems to take place in each kind of affected/infected cell. In fact, it might explain the significance of
myocardial alterations as well as the damage to blood vessels and neurons, where autophagy is critical
to promote cell survival and modulation of inflammatory phenomena. In this scenario, it is fascinating
how concepts from immune-hematology invading neuroscience might contribute to dissecting the role
of cell-clearing systems during COVID-19 pathogenesis. Just like that described for viral infections,
both autophagy and proteasome are key to prevent the accumulation and propagation of prionoids,
such as alpha-synuclein, in either the CNS milieu or distant organs [251], while the immunoproteasome
recruited under pro-inflammatory conditions cleaves alpha-synuclein, specifically within antigenic
sites [141]. While serving as an alarmin for immune defense recruitment, this makes neurons and glia
susceptible to cytotoxic immune attack [141]. Similar to NLRP/HMGB1, which propagates following
an autophagy impairment during viral infections, prionoids and AGEs behave as DAMPs to trigger
inflammatory reactions within host cells, via RAGEs and TLRs [48].
These concepts might also explain the widespread beneficial effects of a variety of phytochemical
compounds that enhance autophagy, while blunting the (immuno-)proteasome. When focusing
individually on each compound, shared molecular targets emerge bridging the pathogenesis
of inflammation with autophagy and immunoproteasome alterations, including p38MAPK,
PTEN/AKT/mTOR, NF-kB, and HMGB1/NLPR/TLR/RAGE axis. This might support the potentially
synergistic, beneficial effects of phytochemical-rich formulations in multisystem viral infections
involving the respiratory, cardiovascular, and nervous system, where the cell-clearing pathways are
ubiquitously altered. Specific phytochemical-induced molecular pathways implicated in autophagy
activation are also involved in blunting immunoproteasome activity. This suggests that the interplay
occurring between autophagy and UPS/immunoproteasome also deserves to be investigated in the
light of their contribution to pneumonia, ALI/ARDS, myocarditis, vasculitis, and neuro-inflammation,
which take place during COVID-19. Despite COVID-19 representing a novel scenario that remains
to be fully characterized from a molecular viewpoint, the findings here discussed suggest that
polyphenol-rich formulations might counteract viral infections by promoting anti-inflammatory and
immuno-modulatory effects that are bound, at least in part, to the tuning of autophagy and proteasome
pathways. in addition to the specific compounds reviewed here, a plethora of additional herbal and
nutraceutical compounds show anti-viral and widespread anti-inflammatory/anti-oxidant effects that
are associated with cell-clearing systems [31,86,252,253]. These include, among others, spermidine,
curcumin, epigallocatechin-gallate, melatonin, eugenol, and vitamin D, which similarly deserve to be
investigated. Experimental and clinical studies subjected to rigorous scientific scrutiny are needed to
confirm whether these phytochemicals might provide prophylactic or adjunct therapeutic support in
COVID-19 pathogenesis, potentially by acting as natural-based, non-toxic autophagy/UPS modulators.
Author Contributions: Writing—original draft preparation, F.L., and F.F.; writing—review, editing, F.L. C.L.B.;
F.B., G.L., M.F., S.S. (Sonia Schiavon), S.S. (Sebastiano Sciarretta), and G.F.; artwork, F.L.; supervision, F.F., S.S.
(Sebastiano Sciarretta) and G.F. All authors have read and agreed to the published version of the manuscript.
Funding: The present work was funded by Ministero della Salute (Ricerca Corrente 2020) and University of Pisa,
Department of Translational Research and New Technologies in Medicine and Surgery (Department Funds 2020).
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
3-MA 3-Methyladenine
ACE(2) angiotensin-converting enzyme (type 2)
AGE advanced glycation end products
AKT protein kinase B
ALI acute lung injury
AMBRA1 activating molecule in beclin-1 regulated autophagy
AMPK 5′ AMP-activated protein kinase
Ang II angiotensin II
ARDS acute respiratory distress syndrome
AT1R angiotensin II receptor type 1
ATG1/ULK1 Unc-51 like autophagy activating kinase-1
BBB blood-brain barrier
BECN1 beclin 1
CNS central nervous system
COVID-19 coronavirus disease 2019
CoVs coronaviruses
COX2 cyclooxygenase 2
DAMP damage-associated molecular patterns
ER endoplasmic reticulum
ERK/MAPK extracellular signal-regulated kinase/mitogen-activated protein kinase
HMGB1 high mobility group box 1
IFN interferon
IL interleukine
JAK/STAT janus kinase/signal transducer and activator of transcription
LMP7 low-molecular mass protein-7 also known as B5i
LPS lipopolysaccharide
MCP-1 monocyte chemoattractant protein-1
MERS-CoV middle east respiratory syndrome coronavirus
MHC-I/II Major histocompatibility molecules class I/II
MODS multiple organ dysfunction syndrome
mTORC1 mammalian target of rapamycin complex 1
MVBs multivesicular bodies
NF-kB nuclear factor kappa-light-chain-enhancer of activated B cells
NLRP3 NOD-, LRR- and pyrin domain-containing protein 3
Nrf2 nuclear factor erythroid 2-related factor 2
p38MAPK p38 mitogen-activated protein kinase
PGC-1α peroxisome proliferator-activated receptor gamma coactivator 1-alpha
PI3K phosphatidylinositol 3-kinase
PKC protein kinase C
PTEN phosphatase and tensin homolog
Rab GTPases G coupled Ras-related proteins in brain
RAGE receptor for advanced glycated end products
RAS renin-angiotensin-system
Rb retinoblastoma
RhoA ras homolog gene family member A
ROS reactive oxygen species

SARS-CoV severe acute respiratory syndrome coronavirus
SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
SIRT1 sirtuin-1
SNARE soluble N-ethylmaleimide-sensitive factor attachment protein receptor
SQSTM1/p62 sequestosome 1
STX17 syntaxin-17
TFEB transcription factor EB
THM traditional herbal medicine
TLR toll-like receptor
TNF tumor necrosis factor
TRAF6 TNF receptor-associated factor
UPS ubiquitin-proteasome system
VPS34 vacuolar protein sorting 34
vRNP viral ribonucleoprotein
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Cell Clearing Systems As Targets of Polyphenols in Viral Infections Potential Implications For COVID-19 Pathogenesis

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Cell Clearing Systems As Targets of Polyphenols in Viral Infections Potential Implications For COVID-19 Pathogenesis

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Cell Clearing Systems as Targets

Keywords: autophagy; immunoproteasome; coronavirus; inflammation; resveratrol; quercetin;

Antioxidants 2020, 9, 1105; doi:10.3390/antiox9111105 www.mdpi.com/journal/antioxidants

adaptive immunity, by modulating constitutive inflammatory responses while ensuring antigen

2.1. Autophagy, Viral Infection, and Inflammation

and reintroduced in cellular metabolism. Different nutrient-sensing pathways convey signals to

counteracting the COX2-NF-kB-NLRP3 pathways [41,110,111]. Rescuing autophagy might produce

2.2. Immunoproteasome, Viral Infection, and Inflammation

that an autophagy impairment might contribute to exacerbating immunoproteasome-dependent

Remarkably, the immunoproteasome-dependent editing and loading of viral antigens on

2.3. Autophagy Impairment, Exosome Release, and Inflammation

Figure 5. Summary of the potential mechanisms underlying SARS-CoV-2-induced alterations of

3.2. Quercetin and Kaempferol

the widespread, anti-inflammatory, and autophagy-related effects of quercetin and kaempferol in a

3.4. Baicalein and Baicalin

Phytochemical Autophagy-Related Effects UPS-Related Effects Anti-Inflammatory Anti-Viral Anti-Apoptotic

Phytochemical Autophagy-Related Effects UPS-Related Effects Anti-Inflammatory Anti-Viral Anti-Apoptotic

ROS reactive oxygen species

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